Quinazoline derivatives useful as anti-tumor medicament

ABSTRACT

The present invention relates to quinazoline derivatives of the formula (I) useful as anti-tumor medicaments, or a pharmaceutically acceptable salt thereof, the definition of the substituents R1, R1′, R2, R2′ are as defined in the description. It also relates to a pharmaceutical composition containing same, and a method for the preparation of quinazoline derivatives of formula (I) or a pharmaceutically acceptable salt thereof.

FIELD OF THE INVENTION

The present invention relates to compounds usable as irreversibleinhibitors of tyrosine kinase, especially to quinazoline derivatives.The invention also relates to the method for preparing the compounds,and to a pharmaceutical composition comprising the said quinazolinederivatives.

BACKGROUND OF THE INVENTION

Cancer is regarded as a disease in the intracellular signal transductionsystem or in the mechanism of the signal transduction. The cell acceptsmany extracellular orders and decides whether or not to proliferate. Theaim of the signal transduction system is to accept these or othersignals from the cell surface, and to transfer them into cells. And thenthese signals are conducted to cell nucleus, cytoskeleton and thestructure for transportation and protein synthesis.

The most common pathogenesis for cancer is a series of defects. Thementioned defects can be that of some proteins (when mutation occurs) orthe defects in the regulation of the amount of the intracellularprotein, which result in excessive or deficient production of theproteins. Generally, the constitutive state can be induced by asignificant trauma in a cell, and a signal for proliferation is thusreceived by the cell nucleus, while this signal is inexistent in fact.The above mentioned procedure can be mediated by many kinds ofmechanisms. Sometimes, some cells will start producing true growthfactors for their own receptors in unnecessary cases, which is so-calledautocrine loop mechanism.

There are many receptors on the cell surface. The interaction betweenthe growth factors and these receptors is essential for the regulationof normal cellular growth. However, in some cases, the overexpression ormutation of the abnormal receptors will result in uncontrollableproliferation, which may induce tumor growth and cancer at last.

Epidermal cell growth factors receptors (EGFR) are identified as onesignificant driving factor in the process for cellular growth andproliferation. In common cancer, such as non-small cell lung cancer, theepidermal cell growth factors receptors are expressed excessively farabove the normal level. The epidermal cell growth factors receptorsfamily is composed of EGFR (Erb-B1), Erb-B2 (HER-2/neu), Erb-B3 andErb-B4. The epidermal cell growth factors receptors are concerned in theprocess for most cancer, especially colon cancer and breast cancer. Theoverexpression and mutation of the receptors have been proved to be theleading risk factor for a bad-prognosis breast cancer. Besides, it hasbeen verified that each of the above four members of the receptorsfamily can aggregate with another member into a heterodimer, and form asignal delivery complex. Overexpression of more than one member of thisfamily in a malignant tumor will result in a synergistic signaldelivery.

EGFR belongs to the protein tyrosine kinase (PTK) family. The proteintyrosine kinase is an enzyme which catalyzes the transportation ofphosphate groups from ATP to the tyrosine residue located in a proteinsubstrate. Protein tyrosine kinases play important roles in normal cellgrowth. The overexpression of EGFR may cause the activation of receptorswithout ligands and the phosphorylation of some proteins, and then thesignal for cell division is produced. As a result, EGFR may magnify theweak signal excessively by the auto-tyrosine-kinase action, and renderthe overproliferation of cells.

Due to the importantance of the abnormal receptor kinases in themechanism for the onset of cancer, many researches have been involved insearching for specific PTK inhibitors as potential anti-cancer drugsrecently. European patent application 520722A1 discloses certain4-phenylamino-phthalazinone derivatives with inhibitory activity againstPTK. European patent application 566226A1 discloses some4-phenylamino-phthalazinone derivatives with substituents at position 5to position 8 having PTK inhibitory activity. European patentapplication 635498A1 discloses that certain 4-phenylamino-phthalazinonederivatives with various substituents at position 6 and with a halogenat position 7 also possess PTK inhibitory activity.

The international publication WO96/30347 (Chinese patent CN96102992)relates to a series of 4-(substituted-phenylamino)-quinazolinederivatives, the prodrugs and the pharmaceutical acceptable saltsthereof, which are used in treating diseases induced byoverproliferation.

The international publication WO97/38983 (Chinese patent CN97194458)provides the compounds useful as irreversible inhibitors againsttyrosine kinase.

The international publication WO 00/06555 (Chinese patent CN99808949)also relates to certain substituted quinazoline compounds that possessPTK inhibitory activity.

The international publication WO 99/35146 (Chinese patent CN99803887)discloses bicycloheteroaromatics as inhibitors against protein tyrosinekinase.

However, there remains the need in this field for new inhibitorseffective against protein tyrosine kinases.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I, or apharmaceutically acceptable salt, or a solvate thereof,

wherein, R₁ is selected from;

(a) Halogen, C₁-C₄alkyl, C₁-C₄alkyl substituted by halogens,C₁-C₄alkoxy, C₁-C₄alkoxy substituted by halogens, methoxyethoxy,N-morpholinopropoxy, ester group, acylamino or sulfonamide group;

(b) Unsubstituted or substituted phenyl, wherein the substituents are1-3 substituents selected from the group consisting of halogen, —OH,C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄alkyl-OH, C₁-C₄alkoxymethyl, C₂-C₄estergroup, or sulfonate;

(c) Unsubstituted or substituted furyl, Unsubstituted or substitutedthienyl, wherein the substituents are 1-3 substituents selected from thegroup consisting of halogen, —OH, —NH₂, C₁-C₄alkyl, C₁-C₄alkoxy,alkoxymethyl, ester group, or sulfonate; or R₁ is

Wherein R₁ is attached to the ring via oxygen, and X is selected fromfuryl, pyrrolidyl, pyridyl, oxazoline, thiazolyl, or thienyl;

R₁′ is selected from hydrogen, C₁-C₄alkyl, C₁-C₄alkyl substituted byhalogens, C₁-C₄alkoxy, or C₁-C₄alkoxy substituted by halogens;

R₂ is selected from benzyl, mono-, di- or tri-halobenzyl, benzoyl,pyridylmethyl, pyridylmethoxy, benzyloxy mono-, di- or tri-halobenzyloxyor mono-, di- or tri-halophenylsulfonyl, furylmethyl, pyrrolylmethyl,pyrrolylmethoxy, halogen, C₁-C₄alkyl or C₁-C₄alkoxy, wherein the saidphenyl, benzyl, pyridyl, furyl or pyrrolyl may have 1-3 substituentsselected from the group consisting of halogen, —OH, —NH₂, C₁-C₄alkyl orC₁-C₄alkoxy.

R₂′ is selected from benzyl, mono-, di- or tri- halobenzyl, benzoyl,pyridylmethyl, pyridylmethoxy, phenoxy, mono-, di- or tri- halophenoxyor mono-, di- or tri-halophenylsulfonyl, furylmethyl, pyrrolylmethyl,pyrrolylmethoxy, halogen, C₁-C₄alkyl or C₁-C₄alkoxy, wherein the saidphenyl, benzyl, pyridyl, furyl or pyrrolyl may have 1-3 substituentsselected from the group consisting of halogen, —OH, —NH₂, C₁-C₄alkyl orC₁-C₄alkoxy.

The present invention also provides the use of the compounds of thisinvention in the production of anti-tumor medicament.

The present invention also provides a pharmaceutical composition whichcomprises 0.05-100 mg of a compound of formula I, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier,excipient or diluent.

The present invention also provides a method for treating tumor,especially the tumor mediated by protein tyrosine kinases, whichcomprises the step of administering to a patient in need of suchtreatment 0.05-100 mg/kg of body weight daily a compound of formula I,or a pharmaceutically acceptable salt, or a solvate thereof.

The present invention also provides a method for preparing apharmaceutical composition, which comprises the step of mixing acompound of formula I, or a pharmaceutically acceptable salt, or asolvate thereof with a pharmaceutically acceptable carrier, excipient ordiluent, thereby a pharmaceutical composition is formed.

In another preferred embodiment, R₂ is selected from benzyloxy, mono-,di- or tri-halobenzyloxy; and R₂′ is halogen.

In another preferred embodiment, R₁ is selected from halogen,C₁-C₄alkoxy, C₁-C₄alkoxy substituted by halogen, methoxyethoxy,N-morpholinopropoxy, ester group, acylamino, sulfonamide group, phenyl,furyl,

or R₁ is

wherein X is furyl.

In another preferred embodiment, R₁ is an acylamino as follows:

Wherein R₃ is selected from hydrogen, N,N-dimethyl aminomethyl,N,N-diethylaminomethyl, N,N-dipropylaminomethyl or N-morphlinomethyl.

In another preferred embodiment, R₁ is an acylamino as follows:

Wherein R₃ is selected from hydrogen or N,N-dimethyl aminomethyl.

In another preferred embodiment, R₁ is selected from α,β-unsaturatedsulfonamide or aryl sulfonamide, or R₁ is selected from a phenylsubstituted by alkyl, alkoxy, alkoxymethyl, ester group, sulfonate, orhydroxymethyl.

In another preferred embodiment, R₁ is selected from a phenylsubstituted by alkoxy, alkoxymethyl, ester group, or hydroxymethyl.

The preferred compounds of this invention are selected from the groupconsisting of:

-   N-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-acrylamide,-   N-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-4-methylbenzenesulfonamide;-   N-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-E,4-(dimethylamino)-but-2-enamide;-   N-[4-(3-chloro-4-benzyloxy-phenylamino)-quinazolin-6-yl]-E,4-(dimethylamino)-but-2-enamide;-   N-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-7-trifluoro    ethoxy-quinazolin-6-yl}-E,4-(dimethylamino)-but-2-enamide;-   N-{4-[3-chloro-4-(3-fluorobenzyloxy)phenylamino]-7-methoxy-quinazolin-6-yl}-E,4-(dimethylamino)-but-2-enamide;-   N-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-acrylamide;-   N-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-7-chloro-quinazolin-6-yl}-E,4-(dimethylamino)-but-2-enamide;-   N-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-7-chloro-quinazolin-6-yl}-acrylamide;-   O-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylaminio]-quinazolin-6-yl}-acetate;-   4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-hydroxy-quinazoline;-   4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-(3-oxo-butoxy-quinazoline;-   4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-[3-(4-morpholine)-propoxy]-quinazoline;-   4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6,7-dimethoxy-quinazoline;-   4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-bromo-quinazoline;-   4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-(4-methoxy-phenyl)-quinazoline;-   4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-(3-hydroxymethyl-phenyl)-quinazoline;-   4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-(3-acetoxymethyl-phenyl)-quinazoline;-   4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-[3-(3-oxo-butoxy-methyl)-phenyl]-quinazoline;-   4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-(5-hydroxymethyl-furan-2-yl)-quinazoline;-   4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-(5-methanes    ulfonyloxymethylene-furan-2-yl)-quinazoline;-   4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-(5-dimethylaminomethyl-furan-2-yl-methoxy)-quinazoline    or-   4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-(3-(4-morpholino)propoxy]-7-methoxy-quinazoline.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the inhibitory effect of the compound of this inventionagainst the phosphorylation of Erb-B2 kinases.

DETAILED DESCRIPTION OF THE INVENTION

In the present invention,

The term “halogen” includes fluoro, chloro, bromo or iodo, preferablyfluoro, chloro and bromo.

The term “C₁-C₄alkyl” includes methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl, propyl,isopropyl or butyl, more preferably methyl.

The term “C₁-C₄alkoxy” includes methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy,ethoxy, propoxy, isopropoxy or butoxy, more preferably methoxy.

The term “ester group” includes formate, acetate, propionate orbutyrate, preferably acetate.

The term “acylamino” includes formamido, acetamido, propionamido;preferably α,β-unsaturated propionamide.

The term “sulfonamide group” includes methanesulfonylamino,ethanesulfonylamino, propanesulfonylamino, isopropanesulfonylamino;preferably methanesulfonylamino.

The term “phenyl” includes unsubstituted or substituted phenyl, whereinthe substituents are 1-3 substituents selected from halogen, —OH,C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄ alkyl-OH, C₁-C₄alkoxymethyl, C₂-C₄estergroup, or sulfonate, preferably phenyl substituted by alkyl, alkoxy,alkoxymethyl, ester group, sulfonate or hydroxymethyl, more preferablyphenyl substituted by alkoxy, alkoxymethyl, ester group and/orhydroxymethyl.

The term “furyl” includes unsubstituted or substituted furyl, whereinthe substituents are 1-3 substituents selected from halogen, —OH, —NH₂,C₁-C₄alkyl, C₁-C₄alkoxy, alkoxymethyl, C₂-C₄ester group, or sulfonate,preferably furyl substituted by alkyl, alkoxy, alkoxymethyl, estergroup, sulfonate and/or hydroxyl.

The term “thienyl” includes unsubstituted or substituted thienyl,wherein the substituents are 1-3 substituents selected from halogen,—OH, —NH₂, C₁-C₄alkyl, C₁-C₄alkoxy, alkoxymethyl, C₂-C₄ester group, orsulfonate, preferably thienyl substituted by alkyl, alkoxy,alkoxymethyl, ester group, sulfonate, and/or hydroxyl.

The present invention also provides the method for the preparation of acompound of formula I. Generally, the compounds of the present inventionmay be prepared by the nucleophilic reaction between a substitutedquinazoline intermediate and 3-chloro-4-(m-fluorobenzyloxy)-aniline inan organic solvent. The reaction is usually conducted under reflux.After large amount of solid has been deposited, the mixture is filtered,and the filter cake is washed with a small quantity of ethyl acetate anddried under vacuum at 60° C. overnight to obtain the compound of thepresent invention.

In the preparation method of the present invention, every reaction isconducted at a temperature between −10° C. and refluxing temperature.Usually the reaction temperature ranges from the room temperature (about25° C.) to a refluxing temperature, preferably 5 to 100° C., morepreferably 20 to 80′. There is no limitation to the reaction time,generally from 1 min to 24 h, preferably from 1 to 20 hours. The solventused in the reaction is usually inert, such as water, DMF, alcohol (forexample methanol, ethanol and isopropanol).

The compounds of the present invention may be administered to human andanimals, which may be administered via oral, rectal, parenteral (e.g.,intravenous, intramuscular or subcutaneous), local (e.g., powders,ointments or drops), or intratumor. The mentioned compounds may beadministered separately or in conjunction with other pharmaceuticallyacceptable compounds. It is appreciated that the compounds of thepresent invention can be administrated as a mixture.

The solid dosage form suitable for oral use may include capsules,tablets, pills, powders or granules. In such solid dosage form, theactive ingredient may be mixed with at least one conventional inertexcipient (or carrier), such as sodium citrate or dicalcium phosphate;or with a component selected from:

(a) fillers or solubilizers, for example, starch, lactose, sucrose,glucose, mannitol or silicic acid; (b) binders, for example,hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone,sucrose and acacia; (c) humectants, for example glycerol; (d)disintegrants, such as agar, calcium carbonate, potato starch or tapiocastarch, alginic acid, certain composite silicates or sodium carbonate;(e) retarding solvents, for example, olefin; (f) absorbent accelerators,such as quaternary ammonium compounds; (g) moistening agents, such ascetyl alcohol and glycerol monostearate; (h) absorbing agents, such askaolin; and (i) lubricants, such as talc, calcium stearate, magnesiumstearate, solid Polyethylene Glycol, Sodium dodecylsulfate or themixture thereof. A buffer can also be contained in the dosages formssuch as capsules, tablets or pills.

Solid dosage forms, such as tablets, rotulas, capsules, pills andgranules may be prepared from coatings and shells such as entericcoatings or other materials known to those skilled in the art. They caninclude opaque materials. Furthermore, active compounds or compounds inthe composition can be released into certain part of the alimentarycanal in a delayed manner. Examples of usable embedding componentsinclude polymers and waxy substance. If necessary, the active compoundscan also be combined with one or more of excipients above to formmicro-capsules.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, injections ortinctures. Beside active compounds, the liquid dosage form may includeinert diluents conventionally used in this field, such as water or othersolvents, solubilizing agents and emulsifying agents, such as ethanol,isopropanol, ethyl carbonate, ethyl acetate, propylene glycol,1,3-butanediol, dimethylformamide and oil, in particular cottonseed oil,peanut oil, corn germ oil, olive oil, caster oil and sesame oil or themixture thereof.

Beside the inert diluents, the composition may also include auxiliaryagents such as moistening agents, emulsifying agents and suspendingagents, sweetening agents, flavoring agents and flavors.

Beside the active compounds, the suspensions may include suspendingagents, for example, ethoxylated isooctadecanol, polyoxyethylenesorbitol, and dehydrated sorbate, microcrystalline cellulose, methanolaluminium, agar, or mixtures thereof.

Compositions for parenteral injection may include physiologicallyacceptable sterile solutions, dispersions, suspensions or emulsions withor without water, and sterile powders for being reconstituted intosterile injectable solutions or dispersions. Appropriate aqueous ornon-aqueous carriers, diluents, solvents or excipients may includewater, ethanol, polyol and appropriate mixtures thereof.

Dosage forms of the compounds of the invention for local administrationmay include ointments, powders, sprays and inhalants. The activecomponent is mixed with physiologically acceptable carriers and anyantiseptics, buffers, or required propellants if necessary under sterilecondition.

In the present invention, the term “pharmaceutically acceptable salts”means relatively innocuous inorganic acid addition salts or organic acidaddition salts of the compound of the present invention. These salts maybe prepared in situ during the final isolation and purification of thecompounds; or prepared by reacting the purified compounds in a form offree alkali with appropriate organic or inorganic acids and isolatingthe salts formed. Representative salts includes hydrobromide,hydrochloride, sulfate, sulphite, acetate, oxalate, pentanoate, oleate,palmate, stearate, laurate, borate, benzoate, lactate, phosphate,toluene formate, citrate, maleate, fumarate, succinate, tartrate,benzoate, methanesulfonate, gluconate, lactobionate and laurylsulfonateand the like. They may contain cations based on alkali metals andalkali-earth metals, such as sodium, lithium, potassium, calcium,magnesium and the like, and cations of innocuous amine, quarternaryamine, and amine cations, including but not limited to amine,tetramethyl amine, tetraethyl amine, methyl amine, dimethyl amine,trimethyl amine, triethylamine, ethylamine and the like.

The compounds of the present invention can be used to treat a diseasemediated by a protein tyrosine kinase, such as breast cancer, non-smallcell lung cancer, ovarian cancer, stomach cancer, pancreatic cancer andso on.

The advantage of the present invention lies in that the compounds of thepresent invention possess excellent anti-tumor activity and notableinhibitory activity against phosphorylation of Erb-B12.

In conjunction with the following preferred embodiments, the inventionwill be further illustrated. It is appreciated that the examples areillustrative only and would not intend to limit the extent of theinvention. The experiment methods which have been noted without specificconditions are generally carried out in accordance with conventionalconditions, or in accordance with the conditions as instructed by themanufacturers. Unless otherwise indicated, the parts and percents are byweight.

EXAMPLES Example 1 3-chloro-4-(3-fluorobenzyloxy)-aniline

In a 250 mL flask equipped with a reflux condenser,2-chloro-4-nitrophenol 4.65 g (26.6 mmol),1-(bromomethyl)-3-fluorobenzene 3.3 mL (27.0 mmol, 1 eq), K₂CO₃ 9.4 g(54 mmol, 2 eq) and 50 mL of DMF were added and then heated to reflux.The mixture was stirred for 4 h, and then filtered without cooling toremove the solid. The filtrate was cooled to room temperature. 300 mL ofethyl acetate was added to dilute the solution, and washed with waterfor 3 times. The organic phases were combined, dried and concentrated.The resulting residue was purified by column chromatography to obtain asolid product.

The above solid product was added into a 250 ml flask equipped with areflux condenser, reduced iron power 4.7 g (87 mmol), 10 mL of aceticacid and 50 mL of absolute ethanol were then added. The mixture wasstirred under reflux for 5 h, then cooled to room temperature, andextracted with large amount of mixed solvent comprised of water andethyl acetate. The organic phases were combined, washed with NaHCO₃solution for 2 times, dried and concentrated. The resulting residue waspurified by column chromatography to obtain the title compound as brownsolid, total yield: 75%.

¹H-NMR (400 MHz, CDCl₃): δ7.38-7.29(1H, m), 7.23-7.16(2H, m),7.04-6.96(1H, m), 6.79-6.74(2H, m), 6.50(1H, dd, J=2.75 Hz, 8.61 Hz),5.03(2H, s), 3.50(2H, br).

Example 2 3-chloro-4-benzyloxy-aniline

In a 250 mL flask equipped with a reflux condenser,2-chloro-4-nitrophenol 4.65 g (26.6 mmol), benzyl bromide 2.97 mL (27.0mmol, 1 eq), K₂CO₃ 9.4 g (54 mmol, 2 eq) and DMF (60 mL) were added andthen heated to reflux. The procedure was conducted as Example 1, theresidue was purified by column chromatography to obtain the titlecompound as brown solid, total yield: 73%.

¹H-NMR (400 MHz, CDCl₃): δ7.30-7.28(1H, m), 7.23-7.16(2H, m), 7.04-6.96(1H, m), 6.79-6.74(2H, m), 6.50(1H, dd, J=2.75 Hz, 8.61 Hz), 5.03(2H,s), 3.50(2H, br).

Example 3 4-chloro-6-nitro-quinazoline

In a 100 mL flask equipped with a reflux condenser,6-nitro-quinazolin-4-one 2.85 g (15 mmol), phosphoryl chloride 25 mLwere added. The mixture was stirred at 105° C. for 3 h, and then wasdropped into 150 mL of ice water carefully, the squama solid depositedwas filtered out, dried, and identified as the title compound. Yield:78%.

¹H-NMR (400 MHz, CDCl₃): δ9.22(2H, s), 8.74(1H, dd, J=2.57 Hz, 9.16 Hz),8.27(1H, d, J=9.16 Hz).

Example 4 4-chloro-6,7-dimethoxy-quinazoline

In a 100 mL flask equipped with a reflux condenser,6,7-dimethoxy-quinazolin-4-one 4.5 g (20 mmol), phosphoryl chloride (45ml) were added. The mixture was stirred at 105° C. for 2 h, and then waspoured into 100 mL of ice water carefully, and off-white squama solidwas deposited slowly, which was filtered, dried and identified as thetitle compound. Yield: 80%.

¹H-NMR (400 MHz, DMSO): δ8.89(1H, s), 7.47(1H, s), 7.41(1H, s), 4.02(3H,s), 4.00(3H, s).

Example 5 O-(4-chloroquinazolin-6-yl)acetate

In a 100 mL flask equipped with a reflux condenser, 6-acetoxyquinazolone3.06 g (15 mmol), phosphoryl chloride. (35 mL) were added. The mixturewas refluxed at 105° C. for 2 h, and then was taken out and poured into150 mL of ice water carefully. A large amount of solid was depositedslowly, which was filtered, dried, and identified as the title compound.Yield: 74%.

¹H-NMR (400 MHz, CDCl₃): δ9.05(1H, s), 8.11(1H, d, J=9.06 Hz), 8.01(1H,d, J=2.52 Hz), 7.73(1H, dd, J=2.52 Hz, 9.06 Hz), 2.40(3H, s).

Example 64-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-6-nitro-quinazoline

In a flask equipped with a reflux condenser,6-nitro-4-chloro-quinazoline 1.20 g (5.7 mmol) and4-(3-fluorobenzyloxy)-3-chloroaniline 1.37 g (5.6 mmol) were dissolvedinto 80 mL of isopropanol, and the solution was refluxed for 3 h. Then alot of yellow solid was deposited, which was filtered, dried undervacuum, and identified as the title compound. Yield: 67%.

¹H-NMR (400 MHz, CDCl₃): δ11.30(1H, br), 9.54-9.48(1H, m), 8.45-8.41(1H,m), 8.31-8.25(1H, m), 7.98-7.89(1H, m), 7.50-7.47(1H, m), 7.35-7.26(1H,m), 7.05-6.96(1H, m), 6.90-6.80(2H, m), 7.74-7.60(2H, m), 4.84(2H, s).

Example 74-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-6-amino-quinazoline

In a flask equipped with a reflux condenser, the compound obtained inExample 6 1.60 g (3.77 mmol), reduced iron powder 1.05 g (18.85 mmol, 5eq), glacial acetic acid (2 mL) and methanol (40 mL) were mixed. Themixture was refluxed in an oil bath at a temperature of 85° C. for 2.5h. Then the iron powder was filtered of, the filtrate was diluted withethyl acetate, washed sequentially with NaHCO₃ solution and water. Theorganic phase was dried and concentrated to obtain yellow solid, whichwas identified as the title compound. Yield: 61%.

¹H-NMR (400 MHz, DMSO): δ9.32(1H, s), 8.31(1H, s), 8.04(1H, d, J=2.64Hz), 7.73(1H, dd, J=2.64 Hz, 8.80 Hz), 7.54-7.43(2H, m), 7.36-7.28(3H,m), 7.26-7.14(3H, m), 5.57(2H, br), 5.27(2H, s).

Example 8N-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-acrylamide

In a 100 mL flask cooled with an ice-bath, the amino-compound obtainedin Example 7 1.2 g (3.04 mmol), triethylamine 0.61 mL (4.2 mmol, 1.5eq), acrylic chloride 0.25 mL (3.04 mmol, 1 eq) and THF (40 mL) wereadded. The mixture was warmed to room temperature slowly, and threehours later, the reaction was stopped. The reactants were extracted withthe mixed system of ethyl acetate-water, and the organic phases werecombined, dried and concentrated. The resulting residue was purified bythe silica gel column chromatography to obtain 10 g of solid, which wasidentified as the title compound. Yield: 67%.

¹H-NMR (400 MHz, CDCl₃+DMSO): δ68.75(1H, s), 8.60-8.52(2H, m), 7.81(1H,d, J=2.44 Hz), 7.69(2H, s), 7.54(1H, dd, J=2.56 Hz, 8.92 Hz),7.30-7.22(2H, m), 7.18-7.08(2H, m), 6.96-6.86(2H, m), 6.37(2H, d, J=5.86Hz), 5.67(1H, t, J=5.86 Hz), 5.06(2H, s).

Example 9N-{4-[-3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-p-methylbenzenesulfonamide

In a 50 mL flask cooled with an ice-bath, the amino-compound obtained inExample 7 1.2 g (3.04 mmol), triethylamine 1.22 mL (8.4 mmol, 3 eq),p-toluene sulfonyl chloride 0.25 mL (3.04 mmol, 1 eq) and THF (40 mL)were added. The mixture was warmed to room temperature slowly, and threehours later, the reaction was stopped. The reactants were extracted withthe mixed system of ethyl acetate-water, and the organic phases werecombined, dried and concentrated. The resulting residue was purified bythe silica gel column chromatography to obtain 1.0 g of solid, which wasidentified as the title compound. Yield: 67%.

¹H-NMR (400 MHz, DMSO): δ9.52(1H, s), 8.45(1H, s), 8.09(1H, d, J=2.61Hz), 7.95-7.88(3H, m), 7.82-7.77(2H, m), 7.64(1H, d, J=8.80 Hz),7.55-7.44(3H, m), 7.35-7.15(5H, m), 5.25(2H, s), 3.05(3H, s).

Example 10N-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-E,4-(dimethylamino)-but-2-enamide

In a 50 mL flask, 3-N,N-(dimethylamino)-methylacrylic chloride 0.4 g(2.7 mmol) was dissolved into anhydrous THF (10 mL). The solution of thearyl amine obtained in Example 1 1.06 g (2.7 mmol) in 15 mL of anhydrousTHF was added into the flask dropwise with strong stirring at 0° C.,then the solution of 0.2 mL of diisopropylethylamine in 5 mL THF wasadded dropwise with the temperature being kept at 0° C. The mixture wasstirred vigorously in an ice-water bath for 3 hours. Then extracted withthe mixed system of ethyl acetate and water, the water phase was washedwith ethyl acetate-THF for 3 times, and the organic phases werecombined, dried and concentrated. The resulting residue was purified bythe silica gel column chromatography to obtain 0.73 g of solid, whichwas identified as the title compound. Yield: 54%.

¹H-NMR (400 MHz, CDCl₃+DMSO): δ8.77(1H, s), 8.61-8.52(2H, m), 7.80(1H,d, J=2.44 Hz), 7.69(2H, s), 7.55(1H, dd, J=2.54 Hz, 8.90 Hz),7.32-7.24(2H, m), 7.18-7.08(2H, m), 7.00-6.86(3H, m), 6.21(1H, dt,J=1.56 Hz, 15.65 Hz), 5.10(2H, s), 3.07(2H, d, J=7.14 Hz), 2.18(6H, s).

Example 11N-[4-(3-chloro-4-benzyloxy-phenylamino)-quinazolin-6-yl]-E-4-(dimethylamino)-but-2-enamide

The procedure in Example 10 was repeated except that the substitutedaryl amine in Example 10 was replace by the compound obtained in Example2. 0.67 g of solid was obtained after silica gel column chromatography,which was identified as the title compound. Yield: 51%.

¹H-NMR (400 MHz, CDCl₃+DMSO): δ8.76(1H, s), 8.60-8.52(2H, m), 7.82(1H,d, J=2.45 Hz), 7.69(2H, s), 7.55(1H, dd, J=2.56 Hz, 902 Hz),7.32-7.24(2H, m), 7.18-7.06(3H, m), 7.00-6.86(3H, m), 6.18(1H, dd,J=1.56 Hz, 15.65 Hz), 5.08(2H, s), 3.10(2H, d, J=7.14 Hz), 2.21(6H, s).

Example 12 N-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-7-trifluoroethoxy)-quinazolin-6-yl}-E-4-(dimethylamino)-but-2-enamide

4-chloro-2-amino-benzoic acid (10.0 g) was dissolved into 50 mL offormamide, the mixture was reacted under reflux for 5 h. A lot of solidwas deposited, which was filtered and dried to obtain 1.5 g of7-chloro-quinazolone.

10 g of the above 7-chloro-quinazolone was added into a mixed acid ofconcentrated sulphuric acid and fuming nitric acid (40 ml) slowly in anice-bath. Then the mixture was heated to 90° C. and reacted at thistemperature for 3 h. The clear solution formed was then poured into 300mL of ice-water carefully, and yellow solid was deposited, which wasfiltered, washed with water and redissolved into hot acetic acid, todeposit the crystalline of 6-nitro-7-chloro-quinazolone, which wascollected and 6.50 g of the product was achieved.

4.00 g of the above crystalline 6-nitro-7-chloro-quinazolone wasrefluxed with 15 mL of phosphoryl chloride for 2 h, then the reactionmixture was poured into ice water, filtered and dried to obtain theintermediate 6-nitro-4,7-dichloro-quinazoline; The intermediate wasdissolved into 30 mL of isopropanol, and 3.00 g of3-chloro-4-(m-fluoro-benzyloxy)-aniline was added. The reaction mixturewas reacted under reflux for 2 h and a lot of solid was deposited, whichwas filtered and dried under vacuum to obtain the solid product of6-nitro-7-chloro-4-amino substituted quinazoline (3.83 g).

2.00 g of above intermediate was dissolved into 50 mL of anhydrous THF,and sodium trifluoroethanoxide (0.64 g) was then added, the reactionmixture was reacted under reflux for 16 h, and 1.78 g of6-nitro-7-trifluoroethoxy-4-amino substituted quinazoline was obtainedafter post treatment.

The above obtained trifluoroethoxy substituted intermediate (1.6 g),reduced iron powder 1.05 g (17.85 mmol, 5 eq), glacial acetic acid (2mL) and methanol (40 mL) were reacted under reflux in an oil-bath for2.5 h, then filtered to remove the Fe powder. The filtrate was dilutedwith ethyl acetate, washed sequentially with NaHCO₃ solution and water.The organic phase was dried and concentrated to obtain 0.90 g of yellowsolid, which was identified as 6-amino-7-trifluoroethoxy-4-aminosubstituted quinazoline. Yield: 61%.

In a 50 mL flask, the above reduced aryl amine (0.50 g) was dissolvedinto anhydrous THF (30 mL), diisopropylethylamine (0.18 mL) and3-N,N-dimethylaminomethylacrylic chloride 0.17 g (1.1 mmol) were addeddropwise sequentially at 0° C. The reaction was kept at 0° C. for 3 h.The reaction mixture was extracted with a mixed system of ethyl acetateand water, the aqueous phase was washed 3 times with ethyl acetate. Theorganic phases were combined, dried and concentrated. The resultingresidue was purified by the silica gel column chromatography to obtainthe title compound as a solid (0.45 g, 72%).

¹H-NMR (400 MHz, CDCl₃): δ8.77(1H, s), 8.61-8.52(2H, m), 7.80(1H, d,J=2.46 Hz), 7.69(2H, m), 7.55(1H, dd, J=2.56 Hz, 8.94 Hz), 7.32-7.24(1H,m), 7.18-7.08(2H, m), 7.00-6.86(3H, m), 6.23(1H, dd, J=1.55 Hz, 15.59Hz), 5.10(2H, s), 4.48(2H, m), 3.11(2H, d, J=7.15 Hz), 2.19(6H, s).

Example 13N-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-E-4-(dimethylamino)-but-2-enamide

The procedure of Example 12 was repeated except that6-nitro-7-chloro-4-[3-chloro-4-(3-fluorobenzyloxy)phenylaminoquinazoline is reacted with the sodium methoxide-methanol system instead oftrifluoroethanol sodium to achieve6-nitro-7-methoxy-4-[3-chloro-4-(3-fluorobenzyloxy)phenylaminoquinazolineas the intermediate; The nitro group of the intermediate was reduced andthen reacted with 3-N,N-dimethylaminomethylacrylic chloride to obtainthe title compound after purification.

¹H-NMR (400 MHz, CDCl₃). δ9.80(1H, s), 9.70(1H, s), 8.91(1H, s),8.50(1H, s), 7.98(1H, d, J=2.44 Hz), 7.69(1H, dd, J=2.44 Hz, 9.16 Hz),7.51-7.42(1H, m), 7.39-7.16(5H, m), 6.90-6.87(1H, m), 6.19(1H, dd,J=2.14 Hz, 10.06 Hz), 5.27(2H, s), 4.02(3H, s), 3.07(2H, d, J=3.8 Hz),2.18(6H, s).

Example 14N-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-acrylamide

The procedure of Example 12 was repeated except that6-nitro-7-chloro-4-[3-chloro-4-(3-fluorobenzyloxy)phenylaminoquinazoline is reacted with the sodium methoxide-methanol system insteadof trifluoroethanol sodium to achieve6-nitro-7-methoxy-4-[3-chloro-4-(3-fluorobenzyloxy)phenylaminoquinazoline as the intermediate; The nitro group of the intermediate wasreduced and then reacted with acrylic chloride to obtain the titlecompound after purification.

¹H-NMR (300 MHz, CDCl₃): δ9.80(1H, s), 9.70(1H, s), 8.91(1H, s),8.50(1H, s), 7.98(1H, d, J=2.44 Hz), 7.69(1H, dd, J=2.44 Hz, 9.16 Hz),7.51-7.42(1H, m), 7.39-7.16(5H, m), 6.75(1H, q, J=10.06 Hz, 16.78 Hz),6.31(1H, dd, J=2.14 Hz, 7.09 Hz), 5.80(1H, dd, J=2.14 Hz, 10.06 Hz),5.27(2H, s), 4.02(3H, s).

Example 15N-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-7-chloro-quinazolin-6-yl}-E,4-(dimethylamino)-but-2-enamide

The procedure of Example 12 was repeated except that the nitro group inthe intermediate6-nitro-7-chloro-4-[3-chloro-4-(3-fluorobenzyloxy)phenylaminoquinazoline was reduced into amino group directly and then the reducedintermediate was reacted with 4-(dimethylamino)-2-butenoyl chloride.Finally the title compound was purified.

Example 16N-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-7-chloro-quinazolin-6-yl}-acrylamide

The procedure of Example 12 was repeated except that the nitro group inthe intermediate6-nitro-7-chloro-4-[3-chloro-4-(3-fluorobenzyloxy)phenylaminoquinazoline was reduced into amino group directly and then the reducedintermediate was reacted with acryl chloride. the title compound wasobtained after purification.

Example 17O-{4-[-3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-acetate

6-acetoxy-4-chloroquinazoline (0.90 g, 4.04 mmol) and3-chloro-4-(m-fluoro-benzyloxy)-aniline (1.00 g, 3.97 mmol) weredissolved into 40 mL of isopropanol, and the mixture was stirred underreflux for 3 h. A lot of light grey solid was deposited, which wasfiltered, and the filter cake was washed with small quantity of ethylacetate and dried under vacuum at 60° C. overnight to obtain the titlecompound (1.65 g, 95%).

¹H-NMR (400 MHz, CDCl₃): δ8.68(1H, s), 7.89-7.81(2H, m), 7.58-7.48(2H,m), 7.40-7.32(1H, m), 7.27-7.19(3H, m), 7.16(1H, d, J=2.46 Hz),7.07-6.96(2H, m), 5.14(2H, s), 2.11(3H, s).

Example 184-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-hydroxy-quinazoline

0.47 g of 6-acetoxy-4-aminoquinazoline intermediate was dissolved into12 mL of methanol, and 1 ml of concentrated ammonia was added dropwise,then yellow solid was deposited immediately. The reaction was carriedout at room temperature for 3 h, and then filtered to obtain part of theproduct. The filtrate was concentrated and purified throughchromatography to obtain another part of product, total 0.41 g, yield97%.

¹H-NMR (400 MHz, CDCl₃): δ8.68(1H, s), 7.88-7.81(2H, m), 7.58-7.48(2H,m), 7.40-7.32(1H, m), 7.27-7.19(3H, m), 7.16(1H, d, J=2.44 Hz),7.07-6.96(2H, m), 5.15(2H, s).

Example 194-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-(3-oxo-butoxy-quinazoline

The 6-hydroxy-4-aminoquinazoline starting material 0.20 g and2-methoxybromoethane 0.07 mL (1.5 eq.) were dissolved into 15 mL of DMF.A catalytic amount of tetrabutylammonium iodide and K₂CO₃ solid 0.14 gwere added, the mixture was reacted at 60° C. overnight. The mixture wasfiltered without cooling, and the filtrate was concentrated to removethe solvent. The resulting residue was purified through columnchromatography to obtain the title compound (0.17 g, 74%).

¹H-NMR (400 MHz, CDCl₃): δ8.67(1H, s), 7.88-7.81(2H, m), 7.56-7.47(2H,m), 7.41-7.32(1H, m), 7.27-7.19(3H, m), 7.15(1H, d, J=2.44 Hz),7.06-6.96(2H, m), 5.16(2H, s), 4.29-4.24(2H, m), 3.85-3.81(2H, m),3.49(3, s).

Example 20 4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-[3-(4-morpholino)propoxy]-quinazoline

The procedure of Example 15 was repeated except that the startingmaterial 6-hydroxy-4-amino quinazoline 0.10 g was reacted with excessive3-(N-morpholino)-1-chloropropene to obtain the title compound (0.09 g,70%).

¹H-NMR (400 MHz, CDCl₃): δ8.69(1H, s), 7.87-7.82(2H, m), 7.55(1H, dd,J=2.56 Hz, 8.87 Hz), 7.46(1H, dd, J=2.56 Hz, 9.17 Hz), 7.40-7.32(1H, m),7.29-7.19(3H, m), 7.16(1H, d, J=2.49 Hz), 7.10-6.96(2H, m), 5.17(2H, s),4.17(2H, t, J=6.45 Hz), 3.74(4H, t, J=4.69 Hz), 2.57(2H, t, J=7.18 Hz),2.50(4H, t, J=4.61 Hz), 2.10-2.01(2H, m).

Example 214-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6,7-dimethoxy-quinazoline

4-chloro-6,7-dimethoxy-quinazoline (1.50 g) and3-choro-4-(m-fluoro-benzyloxy)-aniline (1.70 g) were dissolved into 150mL of isopropanol. The mixture was reacted under reflux for 3 h, and alot of yellow solid was deposited. The precipitated solid was filtered,and the filter cake was washed with cold ethanol and dried at 60° C.under vacuum overnight to obtain the title compound (2.50 g, 84%).

¹H-NMR (400 MHz, DMSO): δ11.30(1H, br), 8.83(1H, s), 8.25(1H, s),7.86(1H, d, J=2.64 Hz), 7.62(1H, dd, J=2.63 Hz, 9.08 Hz), 7.52-7.44(4H,m), 7.23-15(1H, m), 5.30(2H, s), 4.01(3H, s), 3.99(3H, s).

Example 224-[-3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-bromo-quinazoline

6-bormo-4-chloro-quinazoline (1.36 g) and3-choro-4-(m-fluoro-benzyloxy)-aniline (1.42 g) were dissolved into 50mL of isopropanol. The mixture was reacted under reflux for 3 h, and alot of yellow solid was deposited. The precipitated solid was filtered,and the filter cake was washed with cold ethanol and dried at 60° C.under vacuum overnight to obtain the 6-bromo-4-aminoquinazoline product(2.20 g, 86%).

¹H-NMR (400 MHz, DMSO): δ11.33(1H, s), 9.07(1H, s), 8.94(1H, s),8.25-8.16(1H, m), 7.94(1H, d, J=2.64 Hz), 7.85(1H, d, J=9.09 Hz),7.69-7.61(1H, m), 7.53-7.44(1H, m), 7.38-7.29(3H, m), 7.24-7.16(1H, m),5.30(2H, s).

Example 234-[-3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-(4-methoxy-phenyl)-quinazoline

6-bromo-4-aminoquinazoline intermediate (0.30 g) and 4-methoxyphenylboric acid (0.15 g) were dissolved into 20 mL of DMF. Then Pd(PPh₃)4(0.15 g) and Na₂CO₃ (0.14 g) were added thereto under nitrogenatmosphere, and the mixture was reacted at 60° C. for 3 h. The solventwas removed under reduced pressure, and the resulting residue waspurified by column chromatography to obtain the6-(4-methoxy-phenyl)-4-amino substituted quinazoline product (0.21 g,66%).

¹H-NMR (400 MHz, CDCl₃): δ8.78(1H, s), 8.04-7.89(3H, m), 7.85(1H, d,J=2.75 Hz), 7.63-7.53(3H, m), 7.46(1H, m), 7.40-7.32(1H, m),7.27-7.19(2H, m), 7.06-6.96(4H, m), 5.19(2H, s), 3.88(3H, s).

Example 244-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-(3-hydroxymethyl-phenyl)-quinazoline

6-bromo-4-amino substituted quinazoline intermediate (1.50 g) and3-formylphenyl boric acid (1.37 g) were dissolved into 100 mL of1,4-dioxane. Then Pd(PPh₃)4(0.76 g) and 20% aqueous K₂CO₃ solution (5mL) were added thereto under nitrogen atmosphere, and the mixture wasreacted at 60° C. for 0.5 h. The solvent was removed under reducedpressure, and the resulting residue was purified by columnchromatography to obtain a 6-(3-formylphenyl-4-amino substitutedquinazoline intermediate (1.45 g).

The above intermediate was dissolved into a mixed solvent of THF/MeOH(2:1). 0.12 g of NaBH₄ solid was added thereto at 0° C. in portionswhile stirring, and the reaction system turned dark gradually. 30 minlater, most solvent was removed under reduced pressure, and theresulting residue was dissolved into ethyl acetate, the organic phasewas washed with saturated saline, dried and purified by silica gelcolumn chromatography to obtain the title compound (0.82 g, the totalyield of the two steps is 51%).

¹H-NMR (400 MHz, DMSO+CDCl₃): δ9.34(1H, s), 8.40(1H, s), 8.33(1H, d,J=3.69 Hz), 7.75(1H, dt, J=2.02 Hz, 8.56 Hz), 7.65(1H, t, J=2.27 Hz),7.59-7.44(3H, m), 7.39-7.14(1H, m), 7.20-7.03(3H, m), 6.98-6.88(2H, m),6.76-6.67(2H, m), 4.87(2H, s), 4.52(1H, t, J=5.70 Hz), 4.42(2H, d,J=5.70 Hz).

Example 254-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-(3-acetoxymethyl-phenyl)-quinazoline

The 6-(3-acetoxymethyl-phenyl)-4-amino substituted quinazoline material(108 mg) was dissolved into of THF (10 mL), Et₃N (0.19 mL) and acetylchloride (0.03 mL, 1.8 eq.) were added thereto sequentially in anice-bath. The reaction was continued for 3 h, and the achieved productwas purified to obtain the title compound. Yield: 72%.

¹H-NMR (400 MHz, CDCl₃): δ8.79(1H, s), 8.06-7.96(3H, m), 7.86(1H, d,J=2.69 Hz), 7.69-7.48(5H, m), 7.44-7.33(2H, m), 7.26-7.19(1H, m),7.07-6.97(2H, m), 5.20(2H, s), 5.17(2H, s), 2.13(3H, s).

Example 264-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-[3-2-(methoxyethoxymethylene)-phenyl]-quinazoline

The 6-(3-acetoxymethyl-phenyl)-4-amino substituted quinazoline material(112 mg) was dissolved into DMF (10 ml), 2-methoxy-1-bromoethane (0.04mL), Tetrabutylammonium iodide (10 mg) and Potassium carbonate (100 mg)were added thereto. The reaction was heated to 60° C. and continued for8 h, and the title compound was obtained after post-treatment (64 mg,51%).

¹H-NMR (400 MHz, CDCl₃): δ8.67(1H, d, J=2.2 Hz), 7.82(1H, dd, J=2.3 Hz,8.7 Hz), 7.74-7.68(2H, m), 7.60(1H, d, J=7.69 Hz), 7.45(1H, t, J=7.69Hz), 7.39-7.30(2H, m), 7.29-7.19(5H, m), 7.03-6.92(3H, m), 5.01(2H, s),4.78(2H, s), 4.10(2H, t, J=4.95 Hz), 3.69(2H, t, J=4.95 Hz), 3.35(3H,s).

Example 274-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-(5-hydroxymethyl-phenyl)-quinazolineethyl-furan-2-yl)-quinazoline

The 6-bromo-4-amino substituted quinazoline intermediate (3.00 g) and5-formyl-2-furyl boronic acid (1.37 g) were dissolved into 1,4-dioxane(150 mL). Then Pd(PPh₃)4(1.50 g) and 20% aqueous Na₂CO₃ solution (7 mL)were added thereto under nitrogen atmosphere. The reaction was heated to100° C. and continued for 2 h. The solvent was removed under reducedpressure, and the resulting residue was purified by columnchromatography to obtain the 6-[2-(5-formylfuryl)]-4-amino substitutedquinazoline intermediate.

The above intermediate was dissolved into a mixed solvent of THF/MeOH(2:1). NaBH₄ was added thereto at 0° C. in portions, and the reactionsystem turned dark gradually. After 30 min, most solvent was removedunder reduced pressure, and the resulting residue was dissolved intoethyl acetate, washed with saturated saline, dried and purified bysilica gel column chromatography to obtain the title compound (2.18 g,the total yield of the two steps is 70%).

¹H-NMR (400 MHz, CDCl₃): δ9.29(1H, s), 8.36(1H, s), 8.21(1H, d, J=8.38Hz,), 7.73-7.68(1H, m), 7.60-7.58(1H, m), 7.45-7.35(2H, m),7.04-6.96(1H, m), 6.92-6.82(2H, m), 6.70-6.60(2H, m), 6.50-6.47(1H, m),6.08-6.02(1H, m), 4.80(2H, d, J=6.04 Hz), 4.61(1H, t, J=5.63 Hz),4.25(2H, t, J=6.87 Hz).

Example 28 4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-(5-methanesulfonyloxymethylene-furan-2-yl)-quinazoline

The above 6-[2-(5-hydroxymethyl-furyl)-4-amino substituted quinazolinematerial (250 mg) was dissolved into 25 mL of DMF. Et₃N (0.22 mL, 3.0eq.) and methanesulfonyl chloride (0.06 mL, 1.5 eq.) were added theretosequentially at room temperature while stirring. After the reaction wascompleted, the reaction mixture was diluted with large amount of ethylacetate, washed with ice water and saturated aqueous ammonium chloridesequentially, and the organic phase was dried and concentrated. Theresulting residue was purified by column chromatography to obtain thetitle compound (178 mg, 61%).

¹H-NMR (400 MHz, CDCl₃): δ8.66(1H, s), 8.19(1H, d, J=1.18 Hz), 8.03(1H,dd, J=1.57 Hz, 9.00 Hz), 7.91-7.87(1H, m), 7.62-7.55(2H, m),7.40-7.33(1H, m), 7.28-7.20(3H, m), 7.06-7.68(2H, m), 6.77(1H, d, J=3.13Hz), 6.49(1H, d, J=3.52 Hz), 5.17(2H, s), 4.51(2H, s), 3.44(3H, s).

Example 294-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-(5-dimethylaminomethyl-furan-2-ylmethoxy)-quinazoline

5-dimethylaminomethyl-furan-2-yl-methanol oil was obtained according tothe method in the documents wherein dimethylamine, formaldehyde andfurylmethanol were chosen as starting materials. 0.50 g of5-dimethylaminomethyl-furan-2-yl-methanol was dissolved into 20 mL ofCH₂Cl₂. Then Et₃N and Methanesulfonyl chloride were added theretosequentially. 5-dimethylaminomethyl-2-furanmethyl sulfonate was obtainedafter a post-treatment.

The above sulfonate (0.20 g) was dissolved into 20 mL of DMF. Then6-hydroxy-4-amino substituted quinazoline material (0.20 g),tetrabutylammonium iodide (30 mg) and Potassium carbonate (105 mg) wereadded thereto. The mixture was heated to 50° C. and continued for 4 h.The title compound was obtained after post-treatment (129 mg, 48%).

¹H-NMR (400 MHz, CDCl₃): δ8.70(1H, s), 7.88-7.80(2H, m), 7.58-7.48(2H,m), 7.40-7.32(1H, m), 7.27-7.19(3H, m), 7.16(1H, d, J=2.44 Hz),7.07-6.98(2H, m), 6.21-6.18(1H, m), 6.14-6.10(1H, m), 5.19(2H, s),4.64(2H, s), 3.51(2H, s), 2.20(6H, s).

Example 30 4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-(3-(4-morpholino)propoxy)-7-methoxy-quinazoline

6,7-dimethoxy-quinazolone was reacted with methanesulfonic acid andL-methionine under reflux for 2 h, and then the mixture was poured intoice water to deposit a solid, which is 6-hydroxy-7-methoxy-quinazoloneintermediate. After the hydroxyl group therein was protected byacylation, the intermediate was treated with SOCl₂ to obtain4-chloro-6-acetoxy-7-methoxy-quinazoline.

The above moiety was reacted with3-chloro-4-(3-fluoro-benzyloxy)-aniline in isopropanol according to therelated procedure as above to obtain4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-acetoxy-7-methoxy-quinazoline;which was then treated with ammonia and the acetyl was hydrolyzed toobtain the intermediate4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-hydroxy-7-methoxy-quinazoline.

The intermediate was reacted with excessive3-(N-morpholino)-1-chloro-propane according to the procedure of Example15 to obtain the title compound.

¹H-NMR (400 MHz, CDCl₃): δ9.46(1H, s), 8.45(1H, s), 7.95(1H, d, J=2.75Hz), 7.80(1H, s), 7.59(1H, dd, J=2.44 Hz, 8.85 Hz), 7.52-7.44(1H, m),7.39-7.26(3H, m), 7.23-7.15(2H, m), 5.25(2H, s), 4.17(2H, t, J=6.26 Hz),3.93(3H, s), 3.59(4H, m), 2.49(2H, m), 2.39(41H, m), 2.00(2H, m).

Besides, the compound 30a in Table A is obtained in a similar method.

In the present invention, the anti-tumor experiment for the inventivecompounds was conducted as below:

The inventive compounds were formulated into 5 concentrations. Accordingto the improved MTT method of a live cell, 100 μl suspension with aconcentration of 1.0×10⁵ A431 cells (human epidermoid squamous carcinomacell) was inoculated into a 96-well plate, and then the test compoundssolution were added individually until its final concentration; themixture was incubated at 37° C. under humidity for 72 h, the plate wastaken out and MTT was added to each well once again. The incubation wascontinued for another 6 h, and 100 μl SDS was added to end the reaction.The optical density (O. D.) of each well was assayed with an automicroplate reader, and the inhibitory rate was figured out, from whichthe concentration for 50% inhibition (IC₅₀) of each test compound couldbe calculated.

Wherein:

IC₅₀<1 μM was shown as “+++”;

IC₅₀=1-10 μM was shown as “++”;

IC₅₀=10-50 μM was shown as “+”;

IC₅₀>50 μM was shown as “−”. In the anti-tumor experiments for thecompounds of the present invention, the calculated IC₅₀ was shown asfollows:

Example No. IC₅₀ 8 + + + 9 + + 10 + 11 + + 12 + + + 13 + + 14 + + 15 + +16 + + 17 + + + 18 + 19 + + 20 + + + 21 + + 22 + 23 + 24 + + 25 + + +26 + + 27 + + 28 + + 29 + + 30 + +

Example 31 Pharmaceutical Composition

The formulation was as follows:

The compound obtained in Example 8 23 g Starch 140 g microcrystallinecellulose 67 g

According to the general method, the above-mentioned materials weremixed uniformly, and then filled into general gelatin capsules toachieve 1000 capsules.

The capsules of the compound obtained in Example 9 could be prepared insimilar method.

Example 32 1. Cell Line: A431 Human Epidermoid Squamous Carcinoma Cell

The procedure of Example 30 was repeated, and each of the test compoundwas formulated into five concentrations gradually. The 50% inhibitoryconcentration, IC₅₀ was determined. The result of the cell experimentwas shown in Table A.

2. Cell Line: BT-474: Human Breast Cancer Cell

The cells were incubated with compounds of various concentrations(10-0.001 μm individually) for 5 days. The inhibition of cellproliferation was tested according to the SRB method, and the inhibitoryrate was figure out. According to the inhibitory rate, the IC₅₀ wascalculated by the Logit method. The anti-tumor activities in vitro werecompared. The results of the cell experiment were shown in Table A

TABLE A

Compd. A431 BT474 No. R1 R1′ R2 R2′ IC₅₀ IC₅₀  8

H

Cl  0.18,  0.11* 0.001  9

H

Cl 1.22 0.28 10

H

Cl 11

H

Cl 12

Cl 13

Cl 14

Cl 1.72 0.0069 15

Cl

Cl 16

Cl

Cl 17

Cl

H 3.48 0.043 18

H

Cl 19

H

Cl  3.29,  1.70* 0.088 20

H

Cl 1.69 0.079 21

Cl 2.21 0.19 22 Br H

Cl 23

H

Cl  23.97 0.17 24

H

Cl 3.87 0.086 25

H

Cl  2.38,  1.00* 0.062 26

H

Cl 4.04 6.63 27

H

Cl  1.53,  1.03* 0.023 28

H

Cl 2.03 0.049 29

H

Cl 30

Cl 9.26 0.24  30a

Cl 4.47 0.15 Note: The compounds obtained in Example 8-30 are named ascompd. 8-30 respectively. *The two results from two experiments

Example 33

The inhibitory effect of compound 8 and compound 14 on thephosphorylation activity of Erb-B2:

The concentration of the human breast cancer cells BT474 were adjustedto a suitable concentration, and inoculated into a plate. After treatedwith various compounds for 1.5 h, the cells were collected, cracked andthe protein was adjusted to the same quantity. Following theprotein-denaturation, SDS-PAGE was conducted, and transferred to nitricacid cellulose film; Hybriding with the anti-phosphorylation antibody(mono-anti), anti-β-tublin antibody (mono-anti) and anti-mouse-IgGantibody (bi-anti) respectively; Assayed by the ECL kit and the X-rayplate was exposed. According to the size and the density of thecorresponding protein band, the inhibitory effect on Erb-B2 kinases canbe evaluated.

The result was shown in FIG. 1: as compared with the market availabledrug Iressa, compound 8 and compound 14 have more superior inhibitoryactivity.

Example 34

The anti-tumor effect of compound 8 on human skin squamous cancer cellA431 grafted in a nude mouse:

A well-growth solid tumor of A431 was selected and incised into severalpieces with the size of 2-3 mm; each was grafted into the right armpitof a mouse subcutaneously with a trocar respectively. After 7 days, thetest compounds were administrated by gastric perfusion through the mouthfor 13 days continuously. The long span (a) and the short span (b) ofthe tumor were measured with a vernier caliper every 4 days. Accordingto the formula V=ab²/2, the volume (mm³) of the tumor could becalculated. The test animals were neck-off killed 23 days after thegrafting. The test animals were anatomized to obtain the tumor. Thetumors were weighed and the inhibitory rate was calculated.

The result was shown in the table below, which suggests that theinventive compounds have the significant inhibitory effect on the tumor.

Number of test Weight of the Weight of the inhibition Dosage animalstest animals (g) tumor (g) Group (mg/kg) Administration start end(tumor-off) x ± SD % Control 25 ml/kg ig × 13 7 7 22.40 ± 2.81 1.13 ±0.18  (corresponding solvent) Compound 8 25 ig × 13 5 5 21.58 ± 2.180.79 ± 0.20** 29.99 50 ig × 13 5 5 22.87 ± 3.96 0.69 ± 0.17** 38.67 100 ig × 13 5 5 22.13 ± 1.83 0.64 ± 0.23** 43.63

All documents referred to throughout this application are herebyincorporated in their entireties by reference, as if each of them hasbeen individually incorporated. Further, it would be appreciated that,in light of the above described teaching of the invention, those skilledin the art could make various changes and modifications to theinvention, and these equivalents would still fall within the scope ofthe invention as defined by the appended claims of the application.

1. A compound of formula I, or a pharmaceutically acceptable salt,thereof,

wherein R₁ is acylamino of the formula:

wherein R₃ is selected from hydrogen, N,N-dimethylaminomethyl,N,N-diethylaminomethyl, N,N-dipropylaminomethyl and N-morpholinomethyl;R₁′ is selected from hydrogen, C₁-C₄ alkyl, C₁-C₄ alkyl substituted byhalogens, C₁-C₄ alkoxy, or C₁-C₄ alkoxy substituted by halogens, and R₂is selected from benzyloxy, mono-, di- and tri-halobenzyloxy; and R₂′ ishalogen.
 2. A compound of claim 1 or a pharmaceutically acceptable salt,thereof, wherein R₃ is selected from hydrogen andN,N-dimethylaminomethyl.
 3. The compound of claim 1, or apharmaceutically acceptable salt, thereof, which is selected from thegroup consisting of:N-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-acrylamide;N-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-E,4-(dimethylamino)-but-2-enamide;N-[4-(3-chloro-4-benzyloxy-phenylamino)-quinazolin-6-yl]-E,4(dimethylamino)-but-2-enamide;N-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-7-trifluoroethoxy-quinazolin-6-yl}-E,4-(dimethylamino)-but-2-enamide;N-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-E,4-(dimethylamino)-but-2-enamide;N-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-acrylamide.4. A pharmaceutical composition, comprising 0.05-100mg of a compound ofclaim 1, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier, excipient or diluent.